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Abstract

Introduction

The aim of this study was to examine whether the patterns of diffusion-weighted imaging
(DWI) abnormalities and quantitative regional apparent diffusion coefficient (ADC)
values can predict the clinical outcome of comatose patients following cardiac arrest.

Methods

Thirty-nine patients resuscitated from out-of-hospital cardiac arrest were prospectively
investigated. Within five days of resuscitation, axial DWIs were obtained and ADC
maps were generated using two 1.5-T magnetic resonance scanners. The neurological
outcomes of the patients were assessed using the Glasgow Outcome Scale (GOS) score
at three months after the cardiac arrest. The brain injuries were categorised into
four patterns: normal, isolated cortical injury, isolated deep grey nuclei injury,
and mixed injuries (cortex and deep grey nuclei). Twenty-three subjects with normal
DWIs served as controls. The ADC and percent ADC values (the ADC percentage as compared
to the control data from the corresponding region) were obtained in various regions
of the brains. We analysed the differences between the favourable (GOS score 4 to
5) and unfavourable (GOS score 1 to 3) groups with regard to clinical data, the DWI
abnormalities, and the ADC and percent ADC values.

Results

The restricted diffusion abnormalities in the cerebral cortex, caudate nucleus, putamen
and thalamus were significantly different between the favourable (n = 13) and unfavourable
(n = 26) outcome groups. The cortical pattern of injury was seen in one patient (3%),
the deep grey nuclei pattern in three patients (8%), the cortex and deep grey nuclei
pattern in 21 patients (54%), and normal DWI findings in 14 patients (36%). The cortex
and deep grey nuclei pattern was significantly associated with the unfavourable outcome
(20 patients with unfavourable vs. 1 patient with favourable outcomes, P < 0.001). In the 22 patients with quantitative ADC analyses, severely reduced ADCs
were noted in the unfavourable outcome group. The optimal cutoffs for the mean ADC
and the percent ADC values determined by receiver operating characteristic (ROC) curve
analysis in the cortex, caudate nucleus, putamen, and thalamus predicted the unfavourable
outcome with sensitivities of 67 to 93% and a specificity of 100%.

Conclusions

The patterns of brain injury in early diffusion-weighted imaging (DWI) (less than
or equal to five days after resuscitation) and the quantitative measurement of regional
ADC may be useful for predicting the clinical outcome of comatose patients after cardiac
arrest.

Introduction

Although advances in cardiopulmonary resuscitation and critical care medicine have
considerably increased the chances of patient survival after cardiac arrest, most
of these patients suffer ischemic brain injury and often remain comatose for some
time [1]. The degree of cerebral damage must be determined as early as possible to plan and
administer appropriate post-resuscitation therapy and to support the counseling of
family members, but it is often difficult to achieve with certainty [2]. Various methods have been assessed for predicting the neurological outcome of comatose
survivors after cardiac arrest, including clinical examination, electroencephalogram,
somatosensory evoked potentials (SSEPs), and biochemical markers. However, despite
improvements in early prognostic evaluation, there are still some limitations and
defects to solve, such as clinical examination and electroencephalogram being difficult
to apply under sedative treatment [3], SSEPs having a moderate sensitivity in spite of 100% specificity for the prediction
of persistent coma [4], and biochemical markers being susceptible to false positive results [5].

Neuroimaging, such as computed tomography (CT) scans or magnetic resonance imaging
(MRI), is useful in assessing the extent of structural brain injury. Yet, evaluating
hypoxic ischemic brain injury with CT or conventional MRI often underestimates the
actual extent of injury in the acute period [6,7]. In contrast to CT and conventional MRI, diffusion-weighted imaging (DWI) can reveal
the acute or early subacute findings following a focal ischemic stroke or global cerebral
hypoxia [7,8], and this technique allows quantitative assessment of the severity of brain damage
by means of measuring the apparent diffusion coefficient (ADC) [9-12].

The patterns and extent of brain injury seen in DWI are associated with clinical outcomes
in neonates with perinatal asphyxia [13] and patients after cardiac arrest [14,15]. DWI abnormalities in large areas including the cerebral cortex, basal ganglia, and
cerebellum suggest devastating diffuse hypoxic ischemic necrosis, whereas a pattern
of DWI abnormality restricted to the basal ganglia or selected cortical regions suggests
mild hypoxic injury. For a patient stricken with an acute ischemic stroke, the severity
of the neuronal injury within a lesion seen by DWI reflects the degree of apparent
diffusion coefficient (ADC) alteration [16]. The ADCs of cortex and basal ganglia measured during the early life (≤ six days)
of neonates suffering with perinatal asphyxia has also been reported to correlate
with the late prognosis [17]. The high cortical signal of DWI with a marked ADC decrease in the early phase of
global cerebral hypoxia correlates with irreversible tissue injury or cortical laminar
necrosis, and it may be an early marker of the clinical outcome [14,15,18,19]. Recently, two studies reported quantitative ADC analyses of the whole brain or regional
brain as a significant prognostic tool for predicting poor outcome in comatose survivors
after cardiac arrest [20,21].

Therefore, the purpose of our study was to examine whether the patterns of DWI abnormalities
and regional ADC values by a regions-of-interest (ROIs)-based method can predict the
clinical outcome of comatose patients following cardiac arrest.

Materials and methods

Subjects

This study was reviewed and approved by the local ethics committee of our university
hospital. Between January 2004 and December 2007, we prospectively studied 39 patients
at St. Mary's Hospital (a tertiary-care university hospital in Seoul, Korea) who survived
an out-of-hospital cardiac arrest. We included the adult patients (≥ 18 years) who
were successfully resuscitated from the cardiac arrest, survived for at least 24 h,
and remained comatose for at least 6 h after return of spontaneous circulation (ROSC)
to avoid transient unconsciousness. The exclusion criteria included cardiac arrest
resulting from intracranial haemorrhage, drug intoxication, trauma or a terminal illness,
a previous history of neurological disease or brain trauma, a lack of informed consent,
and being unavailable for follow-up. The study group included 28 men and 11 women
(mean age: 49.1 years, range: 18 to 89 years) (Table 1).

Table 1. The clinical characteristics of the 39 comatose patients who were resuscitated from
cardiac arrest

The patients were evaluated in terms of age, gender, cause of death, if the collapse
was witnessed, if a bystander performed cardiopulmonary resuscitation (CPR), the initial
electrocardiogram (ECG) on admission, the duration of resuscitation, the Glasgow coma
scale (GCS) score within 6 h after ROSC, the time between MRI and ROSC, and the Glasgow
outcome scale (GOS) score [22]. The resuscitation protocols followed the American Heart Association guidelines [23,24]. If intracranial haemorrhage was suspected, brain CT was examined as soon as possible
after resuscitation. All of the patients were admitted to an intensive care unit (ICU),
and they received standard intensive care and monitoring, including mechanical ventilation,
arterial catheters, central venous catheters, urinary catheters, and rectal temperature
measurements. Neurological examinations were performed at zero, six hours, one day,
three days, five days, one week and two weeks after cardiac arrest. SSEPs were performed
between one and three days after ROSC. A standardised protocol for therapeutic hypothermia
was used in comatose patients during the latter half of the study period. Eligible
patients underwent therapeutic hypothermia using an external cooling device for 24
h with a target temperature of 33.0 ± 1°C. Slow rewarming to normal temperature was
conducted over eight hours. In patients with therapeutic hypothermia, MRI was performed
after normothermia. All of the patients underwent limited MRI that was confined to
a DWI and a T2-weighted image (T2WI) for rapid image acquisition (<10 minutes) within
five days after resuscitation (the acute and early subacute phases) while avoiding
pseudonormalisation of the DWI [15]. The neurological outcomes of the patients were assessed using the GOS score at three
months after the cardiac arrest. There was no withdrawal of life support. The comatose
patients were divided into two groups: the GOS scores between 1 and 3 (death, vegetative
state, and severe disability) were grouped as unfavourable outcomes; and the GOS scores
of 4 and 5 (moderate disability and good recovery) were grouped as favourable outcomes.
The control group consisted of 16 men and 7 women (mean age: 51.7 years, range: 30
to 80 years) who were examined and scanned at the emergency department for dizziness;
they were free of neurological disorders or brain trauma with normal brain MRIs. Informed
consent was obtained from the patients' relatives and all controls.

Magnetic resonance imaging

In total, 22 of the 39 patients and 23 control subjects were assessed using a 1.5-T
system (Signa Excite; General Electric, Milwaukee, WI, USA) that had echo planar capability.
These studies included the following sequences: the axial fast spin-echo T2WIs (4000/1002/2
[TR/TE/NEX] with a 5 mm section thickness) and the axial DWIs (7000/105.2 [TR/TE],
a section thickness 5 mm, b values of 0 and 1,000 sec/mm2, a field of view 240 × 240, and a matrix size 128 × 128). The other 17 patients were
examined with a 1.5-T system (Magnetom Vision Plus; Siemens, Erlangen, Germany) that
had echo planar capability, with the following sequences: the axial fast spin-echo
T2WIs (4500/99/2 [TR/TE/NEX] with a 5 mm section thickness), and the axial DWIs (5700/139
[TR/TE], a section thickness 5 mm, b values of 0 and 1,000 sec/mm2, a field of view 240 × 240, and a matrix size 96 × 128). The ADC maps were automatically
generated. Only the DWI data and ADC maps were analysed for this study. The T2WI was
used to detect old hyperintense abnormalities to exclude chronic infarction, or it
was used as a reference image for this study. The MRIs were reviewed on a standard
picture archiving and communication system workstation (Maroview; Marotech, Seoul,
Korea). The DWIs together with the ADC maps of all the comatose patients were jointly
evaluated by two experienced neuroradiologists blinded to the patients' clinical data.
The brain injuries on DWI were categorised into four patterns on the basis of the
injury region of the grey matter: normal, isolated cortical injury, isolated deep
grey nuclei injury (including caudate nucleus, putamen, and thalamus), and mixed cortical
and deep grey nuclei injuries.

The ADC values were only obtained from 22 patients who were examined using the GE
Signa Excite due to the use of two kinds of MR scanners. On the workstation, the ADC
value of each pixel was constantly displayed on the screen with a movement of a region
of interest (ROI) cursor. For each patient, the region of a high signal on the DWI
and a low signal on the ADC map was identified. The ROIs were positioned on the areas
with a minimum ADC on the ADC maps to produce ADC values for each brain region. If
the brain regions were normal, then the ROIs were positioned on the predefined locations
(Figure 1). The colour shades were used on the ADC maps to visualise the degree of ADC decrease.
Regions of low ADC showed a blue colour; in contrast, regions of high ADC showed a
white colour (Figure 2). The colour shades on the ADC maps identified the pixel showing the minimum ADC
value in each brain region. The ADC measurements from both sides of the brain were
averaged as a patient's ADC value or a control ADC value. ROI sizes varied by region,
using 4 mm2 for cortex, 10 mm2 for the caudate nucleus and putamen and 25 to 40 mm2 for the subcortical white matter, thalamus, cerebellum, and pons. The percentage of
the patient's ADC, as compared to the average normal control ADC in 15 different brain
regions, was computed as a percent ADC value. The person placing the ROIs was blinded
to the patient's outcome. To ensure accurate localisation and consistency of the measurements,
the ROIs were carefully placed by a single analyst (SPC) who worked in consultation
with a neuroradiologist who had 15 years of experience reading MRIs.

Figure 2.Apparent diffusion coefficient map with colour shades (A), diffusion-weighted imaging
(B) and T2-weighted image (C) from one representative patient at seven hours after
cardiac arrest. Regions of low apparent diffusion coefficient (ADC) showed a blue colour; in contrast,
regions of high ADC showed a white colour. The colour shades on the ADC maps identified
the pixel showing the minimum ADC value in each brain region. A 3D cursor (arrow)
was used to select the predefined spot (right thalamus) simultaneously in the three
different sequences, and it can be easy to mark the area with the minimum ADC on the
ADC maps based on the T2-weighted image (T2WI) and diffusion-weighted imaging (DWI).
The circular region-of-interest (ROI) cursors were positioned on the areas with the
minimum ADC in each brain region. Severely restricted diffusion within the ROIs was
shown in the caudate nucleus (0.238 × 10-3mm2/sec), putamen (0.299 × 10-3mm2/sec), thalamus (0.290 × 10-3mm2/sec), and occipital grey matter (0.184 × 10-3mm2/sec) but not in the occipital white matter (0.712 × 10-3mm2/sec).

Statistical analyses

The data were expressed as means ± standard deviations. Chi-squared and Fisher's exact
tests were used to assess qualitative data (clinical: gender, witnessed arrest, bystander
CPR, initial ECG on admission, and cause of arrest; MRI: abnormalities of each region
of brain). T-tests were used to compare the quantitative data (clinical: age, resuscitation duration,
and time between MRI and ROSC). A one-way ANOVA with the Scheffe post hoc test was
applied to study the ADC values in the different regions of the brain. Box and whisker
plots were constructed to summarise the distributions of the percent ADC values for
the control, the favourable and the unfavourable outcome groups. Spearman's correlation
test was used to correlate GOS at three months after ROSC with ADC values of each
brain region. Correlations between ADC values of each brain region used a Pearson's
correlation. Sensitivity, specificity, positive predictive values (PPV), and negative
predictive values (NPV) for predicting unfavourable outcome were calculated using
the optimal cutoff values determined by ROC curve analysis. The cutoff level predicting
unfavourable outcome with 100% specificity was considered to be optimal. A P value of < 0.05 was considered significant. Statistical analysis was performed using
the Statistical Package for Social Sciences (SPSS) version 15.0 (SPSS Inc., Chicago,
IL, USA).

Results

General characteristics

During the study period, 240 patients unrelated to trauma suffered out-of-hospital
cardiac arrest with attempted resuscitation. Of them, 131 achieved ROSC for more than
20 minutes, and 89 patients were admitted to the hospital alive. Sixty-five patients
remained comatose for at least 6 h and survived for more than 24 h after admission.
Of the 65 patients, 26 were excluded from this study as follows: lack of MRI data
because of early death before MRI (n = 10); MRI delay over five days after ROSC (n
= 3); no informed consent (n = 4); cardiac arrest due to intracranial haemorrhage
(n = 12); and previous history of Parkinson's disease (n = 1), brain operation (n
= 2), or cerebral infarction (n = 1). Thus, 39 were included in this study; 13 patients
were assigned to the favourable outcome group (GOS 4 to 5), and 26 were assigned to
the unfavourable outcome group (GOS 1 to 3). The mean time to MRI after ROSC for the
patients was 52.9 ± 37.5 hours (range, 6 to 119 hours). The clinical characteristics
of the patients are summarised in Table 1. There were no significant differences between the two groups, except for the initial
ECG rhythm on admission. The mean duration in the intensive care was 11.5 ± 7.6 days
(range, 3 to 31 days) in patients with favourable outcome and 21.1 ± 19.6 days (range,
2 to 91 days) in patients with unfavourable outcome. Ten patients (25.6%) died with
a mean survival period of 9.2 ± 8.0 days (range, 2 to 29 days). Therapeutic hypothermia
was performed in 15 (38%) of 39 analysed patients and 4 of the 15 patients had a favourable
outcome. Myoclonic or seizure activities were seen within the first three days after
ROSC in 15 patients (38.4%). Of 15 patients, 10 had an unfavourable outcome. Pupillary
light reflex was often seen within first three days in patients with both favourable
and unfavourable outcome. Eleven patients (28%) who showed loss of pupillary light
reflex had an unfavourable outcome. Motor response to pain was absent at three days
after cardiac arrest in 15 patients (38%) who had an unfavourable outcome. For 20
(51%) of 39 patients, CT scans were performed within 3 h after the event, and the
scans were read as normal for 15 patients. The CT scans of the other five patients
were interpreted as having brain edema, and they had an unfavourable outcome. In 20
(51%) of 39 patients, SSEP was examined between one and three days after cardiac arrest.
Of them, eight patients who showed no cortical response had an unfavourable outcome.

Qualitative analysis of the DWI

The cortex and basal ganglia were frequently damaged in the patients but predominantly
in the unfavourable outcome group (81% vs. 8%, P < 0.001; and 77% vs. 23%, P = 0.002, respectively). In terms of cortical injuries, the Rolandic (precentral and
postcentral), occipital, and parietal cortices had more frequent injury than did the
frontal and temporal cortices. The cerebellum and pons had no differences in DWI abnormalities
between the favourable and unfavourable outcome groups. The subcortical white matter
had no DWI abnormality in any of the patients (Table 2). The neurological outcome in relation to DWI patterns is shown in Table 3. The cortical pattern of injury was seen in one patient (3%), the deep grey nuclei
pattern was seen in three patients (8%), the cortex and deep grey nuclei pattern was
seen in 21 patients (54%), and normal DWI findings were seen in 14 (36%). There were
significant differences in the number of patients with normal findings or mixed cortex
and deep grey nuclei injuries between the two groups (Fisher's exact test, P < 0.001). However, the cortical pattern and the deep grey nuclei pattern had no difference
in the clinical outcome between the two groups.

Table 3. Patterns of diffusion-weighted imaging abnormalities in the two outcome groups

Quantitative analysis of the ADC values

ROI analysis

The ADC value was measured in 22 patients: 8 had a favourable outcome, and 14 had
an unfavourable outcome. Among the grey matter structures of 22 patients, the precentral
cortex showed the lowest mean ADC value (0.598 ± 0.234 × 10-3 mm2/sec), whereas the temporal cortex had the highest mean ADC value (0.710 ± 0.277 ×
10-3 mm2/sec). In all regions, the mean ADC values of the favourable outcome group were similar
to those of the controls. The favourable outcome group had significantly different
mean ADC values and percent ADC values than the unfavourable outcome group in the
frontal, parietal, temporal, occipital, precentral, and postcentral cortices, the
caudate nucleus, the putamen, and the thalamus (Table 4) (Figure 3) (P < 0.05). The unfavourable outcome group had significantly different mean ADC values
than the controls in the frontal, parietal, temporal, occipital, precentral and postcentral
cortices, the frontal white matter, the caudate nucleus, the putamen, and the thalamus
(P < 0.05).

Figure 3.Boxplot showing the distribution of the percent apparent diffusion coefficient values
for the different brain regions of the control (white bars), favourable (striped bars),
and unfavourable (grey bars) groups. The percent apparent diffusion coefficient (ADC) values were calculated using the
mean normal control value of each brain region.

Table 4. The ADC values of the individual brain regions in the patients and the control subjects
(mean ADC ± SD; × 10-3mm2/sec)

In order to predict the unfavourable outcome, the optimal cutoffs for the mean ADC
and the percent ADC values in the grey matter structures were derived from the ROC
curve analysis (Table 5). The areas under the ROC curve were greater than 0.9 for ADC values in the parietal,
occipital and precentral cortices, putamen, and thalamus (all P < 0.001). The optimal cutoffs for the mean ADC and the percent ADC values in each
cortex, caudate nucleus, putamen, and thalamus predicted the unfavourable outcome
with sensitivities of 67 to 93% and a specificity of 100%. In particular, the cutoffs
of the occipital cortex and putamen produced the highest accuracy (Table 5).

Table 5. Prediction of unfavourable outcome using the optimal cutoffs of the ADC and the percent
ADC

Discussion

The results of this study suggest that the pattern of brain injury on early DWI (≤
five days after resuscitation) and quantitative measurements of regional ADC may help
predict the clinical outcome of comatose patients after cardiac arrest. Conventional
MRI is not a helpful prognostic tool in the early phase after global cerebral hypoxia
because it may reveal normal or only subtle abnormality [7,15]. Conversely, DWI could give prognostic values for comatose patients because it is
very sensitive for detecting cerebral ischemia [14,15,18,19]. DWI provides an approximation of the water motion in brain tissue. In early anoxic
encephalopathy, a dysfunction of the membrane bound Na-K-ATPase pump is caused by
ischemia and this leads to a shift of water from the extracellular compartment to
the intracellular compartment, which restricts intracellular water motion [25,26]. This restricted diffusion is markedly hyperintense on DWI. DWI can show the restricted
diffusion associated with acute ischemia 30 minutes after a witnessed ictus in the
patients with acute stroke. The ADC is most reduced at 8 to 32 h and remains markedly
reduced for three to five days [26]. Therefore, DWI may be of greater diagnostic utility to detect cerebral ischemia
within five days after the event [15,18].

Findings of this study have shown that different patterns of brain injury relate to
clinical outcome. Diffusion abnormality of the cortex was mainly observed in the unfavourable
outcome group. Most of the patients with cortical abnormalities also had combined
deep grey nuclei abnormalities. Thus, the mixed pattern of injury (cortex and deep
grey nuclei) often showed diffuse and bilateral abnormalities and seems to correlate
with the most severe brain injury of postcardiac arrest survivors [14,15]. Therefore, the mixed pattern of injury was most predictive of an unfavourable outcome,
although one patient, whose DWI showed subtle abnormalities in the cortex and basal
ganglia, had a good neurological recovery in this study. On the other hand, a normal
finding of DWI indicated a high probability of a favourable outcome. Among 14 patients
with normal DWI findings, four patients had an unfavourable outcome. One of these
four patients died due to massive haemoptysis during the ICU stay. Another patient
suffered from chronic renal failure before the cardiac arrest, which contributed to
the unfavourable outcome. However, the two patients did not have any specific cause
having an unfavourable outcome, suggesting that the normal finding of DWI is not always
associated with a favourable outcome [17,27,28].

Concerning the location of cortical injury, the Rolandic, parietal, and occipital
cortices were more frequently injured than were the frontal and temporal cortices,
which is consistent with findings in previous studies [14,27]. This result suggests that the Rolandic, parietal, and occipital cortices are most
affected by global cerebral hypoxia. In the Rolandic cortex, many net-associated pyramidal
cells predominantly populate layers III and V, which are vulnerable to hypoxia [29]. The occipital lobe and the precuneus are known to be supplied by the posterior cerebral
artery and partly by the anterior cerebral artery, and these arteries intermingle
for anastomosis in the medial parietal lobe. For both arteries, the occipital lobe
and the precuneus are the last border zone of the brain artery network [30]. Therefore, hypoxic ischemic injuries may specifically induce neuronal death in these
areas.

In this study, the ROIs were not positioned in the same location for all the patients
and were located in the visually abnormal areas seen on DWI. This may have induced
significant bias because the normal ADC values are not homogeneous in the different
regions of the brain. However, Helenius et al. [31] demonstrated in a study of 80 healthy volunteers that the ADC values alone were not
site-specific, and no differences were found in the various cortical grey matter and
white matter regions. Therefore, although the ROIs in this study are not positioned
in the same location of brain, the ADC value for each region can be thought to be
a representative value for each patient. The reported normal ADC values in the grey
matter and white matter were 0.78 to 1.09 × 10-3 mm2/sec and 0.62 to 0.79 × 10-3 mm2/sec, respectively [31]. These values are similar to our control ADC values. However, the control ADC values
in the Rolandic cortex (0.65 to 0.80 × 10-3 mm2/sec) were lower than those in the other cortices and were similar to those in the
subcortical white matter, which might be explained by the low signal intensity in
the perirolandic cortex of the normal brain on the T2WI and the fluid attenuated inversion
recovery (FLAIR) images due to the histologic background [32,33].

The high cortical signal on DWI during the early phase of global cerebral hypoxia
correlates with irreversible tissue injury or cortical laminar necrosis. Kawahara
et al. [34] reported that DWI showed hyperintensity in the cerebral cortex of vegetative patients
on Day 3, and laminar hyperintensity was observed in the same area on the T1-weighted
images on Day 14. Thus, DWI can be very useful for detecting cortical laminar necrosis
in patients with anoxic hypoxic encephalopathy in the early subacute phase (one to
five days) [19]. Lovblad et al. [19] demonstrated that in 19 patients with cortical laminar infarcts, the ADC value decreased
to 60 to 80% of the normal value in the bilateral or localised cortical lesions seen
on DWI, and all of the patients were dead or survived with severe disabilities. Els
et al. [14] also reported that in 9 of 12 patients with global cerebral hypoxia, the ADC values
of the cortex were reduced to 60 to 80% of the normal value on DWI within 36 h after
cardiac arrest, and this led to a vegetative state after six months. In our study,
the ADC values in the grey matter structures (including the cortex and deep grey nuclei)
with restricted diffusion decreased to 21 to 79% of that of the controls, and although
the percent ADC values had a wide range, the upper value was approximately 80% of
normal, which was similar to that of the previous studies. In a small study of six
patients with extremely poor outcomes [18], all of them showed a mean ADC value of 0.35 × 10-3 mm2/sec in the precentral cortex in the early phase (one to five days) after a severe
anoxic event, which was comparable with the mean ADC value of 0.42 × 10-3 mm2/sec in the unfavourable outcome group of this study. Thus, ADC values of the grey
matter structures decreased to less than 80% of normal may indicate a cortical laminar
necrosis or an irreversible tissue injury and this may well predict an unfavourable
outcome.

The degree of the changes of the DWI and the ADC signal intensity correlates with
the severity of neuronal injury because modest changes reflect signs of ongoing lesions,
and a severe drop of the ADC corresponds to cell death [10]. In this study, high correlations were observed between the GOS and the ADC values
of the parietal and occipital cortices, putamen, and thalamus. The extent of the DWI
abnormalities that occurs with the ADC decrease is of importance to determine the
outcome of patients [14]. Recently, two studies [20,21] evaluated the extent of DWI abnormalities by measuring whole brain ADC values and
the predicted clinical outcome of patients after cardiac arrest. Wu et al. [20] demonstrated in 80 comatose patients with cardiac arrest that a whole-brain median
ADC less than 0.665 × 10-3 mm2/sec was a significant predictor of poor outcome based on no eye opening or a six
month modified Rankin scale score greater than 3. Wijiman et al. [21] reported that the percentage (10% cutoff value) of brain volume below the ADC threshold
of 0.650 × 10-3 mm2/sec differentiated between survivors and patients who died or remained vegetative,
whereas mean brain ADC values did not differentiate between outcome groups in contradiction
to Wu et al.'s results. However, in the setting of hypoxic ischemic encephalopathy
following cardiac arrest, for a patient who has global cerebral injury that is generally
widespread, the severity of the injury may be expressed by the degree of the altered
ADC value in any specific area (for example, the parietal and occipital cortices,
putamen, and thalamus) in the early phase. Therefore, we believe that on the DWI performed
within five days of anoxic encephalopathy, if there is a mixed pattern of injury (cortex
and the deep grey nuclei) and if the ADC value in any grey matter is reduced to less
than 80%, then this may allow us to predict an unfavourable outcome.

There are several limitations of this study. First, two different scanners were used
for the patients, and a smaller number of patients than all of the study patients
were used to determine the cutoff value of the ADC for predicting an unfavourable
outcome. Thus, a larger number of patients are needed to confirm this. Second, ROI-based
analysis was done on the confined areas that showed diffusion restriction. If the
patients had segmental infarction with a low ADC in the confined area, this may produce
a bias for predicting clinical outcome. Yet, all patients in this study did not have
any segmental infarction. In 22 patients with ADC measurement, 6 had normal DWI findings,
14 had a bilateral injury of the cortex and deep grey nuclei, and 2 had a bilateral
putamen injury. Third, partial volume averaging of the subcortical white matter, which
has a lower ADC value than the grey matter, would be expected to reduce the measured
ADC values of the grey matter. Fourth, although MRI was performed within five days
after ROSC to avoid pseudonormalisation of the DWI, the MRIs were taken at different
times, and this could have influenced the ADC changes due to the evolution of the
abnormality seen on DWI [7,28]. Fifth, this study included patients with or without induced hypothermia, which did
not statistically influence patient outcome. We cannot expect an effect of induced
hypothermia on a brain's ADC abnormality. Sixth, the intensivists who treated the
patients were not kept blinded from the MRI data of the patients, and this data was
used for counseling the patients' families, although there was no withdrawal of life
support. Thus, this could have produced a bias in the patients' treatment by the intensivists.

Conclusions

Our study has revealed that the mixed pattern of brain injury (the cortex and deep
grey nuclei) on DWI performed within five days after cardiac arrest is well-correlated
with an unfavourable outcome. The recognition of brain injury pattern using DWI may
be important to determine clinical outcome of the comatose patients after out-of-hospital
cardiac arrest. In addition, there was a relationship between the GOS and the regional
ADC values of the grey matter structures, in which cutoffs of ADC values were helpful
in discriminating an unfavourable from a favourable outcome. Therefore, the pattern
of brain injury and quantitative measurement of regional ADC may predict the clinical
outcome of comatose patients following their cardiac arrest.

Key messages

• Diffusion-weighted imaging is an important diagnostic method for predicting the
clinical outcome of comatose survivors after out-of-hospital cardiac arrest.

• The cortex and basal ganglia were predominantly damaged in the patients, and in
particular, the Rolandic, parietal, and occipital cortices were most frequently injured
in the patients with an unfavourable outcome.

• The mixed pattern of brain injury (including the cortex and deep grey nuclei) on
DWI in the early phase (less than or equal to five days) of anoxic encephalopathy
was well-correlated with an unfavourable outcome three months after out-of-hospital
cardiac arrest.

• The relationship between the GOS and the regional ADC values of the cortex and deep
grey nuclei was observed, and cutoffs of ADC values discriminated between an unfavourable
and a favourable outcome.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

SPC participated in data collection, analysis and interpretation, and drafted the
manuscript. KNP conceived the study, participated in its design and coordination and
helped to draft the manuscript. HKP collected data. JYK collected and interpreted
radiologic data. CSY collected data and helped with the study design. KJA collected
and interpreted radiologic data. HWY participated in the study design and performed
the statistical analyses. All authors read and approved the final manuscript.

American Heart Association in collaboration with International Liaison Committee on
Resuscitation: Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care:
International Consensus on Science.